Gene transcription is a dynamic process tightly regulated by chromatin, which is a complex structure comprised of DNA and histone proteins.1 The function of gene regulation is controlled by post-translational modification states of DNA-packing histones in the chromatin complex.2 For example, the N-terminal lysine residues of histone proteins can be acetylated and deacetylated to control gene expression via the interplay of a range of enzymes such as histone acetyltransferase (HAT), histone deacetylase (HDAC) and methyltransferase (MT).1 Hence, these enzymes have become the targets of drug discovery efforts.3,4 However, the reader domains that interrogate post-translational modification states have been less intensively pursued as epigenetic targets.5,6 
Acetylated histones are recognized by small protein pockets called bromodomains.7 The bromodomain and extratenninal domain (BET) family of bromodomain-containing proteins (BRD2, BRD3, BRD4 and BRDT) are a class of transcriptional regulators containing tandem bromodomains and a carboxyl-terminal recruitment domain.8,9 In particular, BRD4 plays a significant role in cell cycle progression and viability via its effects on growth-related genes at the M/G1 boundary.10,11 Recently, BRD4 has been shown to play an important role in sustaining the proliferation of metastatic melanoma, a mostly incurable disease, thus rendering it as a possible target for epigenetic therapy.12 
The selective inhibition of the bromodomain 4 (BRD4)/histone interaction has been demonstrated by several small molecule inhibitors such as (+)-JQ1, which is capable of occupying the ε-N-acetylated lysine residue (Kac) binding site of BRD4 and act as a Kac-competitive inhibitor.13 Subsequent reports have shown that (+)-JQ1 can directly regulate transcription mediated by the c-myc gene and reduce the expression of oncogenic c-myc protein.14,15 
The success of the anti-cancer compound cisplatin and its analogues has inspired the investigation of metal-based compounds as therapeutic agents over the past few decades.16-24 While classical metal-based chemotherapeutic agents typically target double-helical DNA, increasing knowledge in molecular biology has uncovered the possibility of specifically targeting therapeutically relevant proteins or enzymes using transition metal complexes.25-29 Metal-based compounds can offer distinct opportunities in targeting proteins or enzymes compared to organic small molecules due to their interesting structural diversity and electronic properties. Moreover, metal complexes can undergo ligand exchange reactions with biomolecules, and such irreversible inhibitors may show enhanced potency and potentially allow for less frequent and lower dosages in vivo.30 Examples of approved drugs that act via a covalent mechanism include EGFR inhibitors neratinib (Pfizer), afatinib/BIBW-2992 (Boehringer Ingelheim) and PF-00299804 (Pfizer), and anti-HCV agents telaprevir (Vertex Pharmaceuticals and Johnson & Johnson) and boceprevir/Victrelis (Merck) (FIG. S1).30 Neratinib, Afatinib/BIBW-2992 and PF-00299804 target cysteine in EGFR and carfilzomib/Kyprolis, a selective proteasome inhibitor, targets threonine, while Telaprevir, used for the treatment of HCV, targets serine. Boceprevir/Victrelis also targets serine of HCV protease, and is used for the treatment of hepatitis caused by HCV,
Metal complexes can adopt a wide range of geometrical shapes defined by the oxidation state of the metal center and the nature of the co-ligands, while organic compounds are mainly restricted to linear, trigonal planar and tetrahedral geometries, Therefore, metal complexes may be able to sample additional chemical space within the active site of enzymes or proteins, In addition, the steric and electronic properties of metal complexes can be easily tuned without lengthy synthetic protocols due to the modular nature of inorganic synthesis, We and others have previously demonstrated that certain Ir(III),31-33 Rh(III)34,35 and Ru(II)36-39 complexes can be developed as inhibitors of enzymes or protein-protein interactions (PPI). In particular, Ma et al Angew. Chem. Int. Ed. Engl, 47, pages 3735-3739 (2008) reported that binds covalently to histidine and generates a luminescence signal.